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J. Biol. Chem., Vol. 279, Issue 47, 49551-49561, November 19, 2004

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Protein Phosphatase 4 Is a Positive Regulator of Hematopoietic Progenitor Kinase 1^*

Guisheng Zhou, Jonathan S. Boomer, and Tse-Hua Tan

From the Department of Immunology, Baylor College of Medicine, Houston, Texas 77030

Hematopoietic progenitor kinase 1 (HPK1) is a hematopoietic specific mammalian Ste20-like protein kinase and has been implicated in many cellular signaling pathways including T cell receptor (TCR) signaling. However, little is known about the in vivo regulation of HPK1. We present evidence that HPK1 is positively regulated by protein phosphatase 4 (PP4; also called PPX and PPP4), a serine/threonine phosphatase. We found that PP4 interacted with HPK1 and that the proline-rich region of HPK1 was necessary and sufficient for this interaction. We also found that PP4 had phosphatase activity toward HPK1 in vivo and that co-transfection of PP4 with HPK1 resulted in specific kinase activation of HPK1. Moreover, we found that the PP4-induced HPK1 kinase activation was accompanied by an increase in protein expression of HPK1. Pulse-chase analysis showed that PP4 increased the half-life of HPK1. Further studies showed that HPK1 was subject to regulation by ubiquitination and ubiquitin-targeted degradation and that PP4 inhibited HPK1 ubiquitination. In addition, we found that TCR stimulation enhanced the PP4-HPK1 interaction and that wild-type PP4 enhanced, whereas a phosphatase-dead PP4 mutant inhibited, TCR-induced activation of HPK1 in Jurkat T cells. Combined with the observation that PP4 enhanced HPK1-induced JNK activation, our studies identify PP4 as a positive regulator for HPK1 and the HPK1-JNK signaling pathway.

Received for publication, September 8, 2004

^* This work was supported by National Institutes of Health (NIH) Grants R01-CA87076 and R01-AI42532 (to T.-H. T.), Beginning Grant-in-Aid 0465156Y from the American Heart Association Texas Affiliate (to G. Z.), and NIH Grant 5-T32-A107495 (to J. S. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Immunology, Baylor College of Medicine, One Baylor Plaza, M929, Houston, TX 77030. E-mail: ttan{at}bcm.tmc.edu.

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